PROJECT SUMMARY Early innate immune response to influenza A infection plays a crucial role in clinical outcome and the development of long term immunity. However, the key mechanisms required for the development of protective immunity and the maintenance of immune homeostasis in the lung are largely unknown. The goal of the proposed U19 center is to examine the dynamic lung response to influenza A virus (IAV) infection via experimental and computational modeling. The research program is based on three distinct yet integrated projects. The objective of project I is to experimentally study the innate response in human epithelial cells using different IAV strains and recombinant viruses as probes. The objective of project II is to study the innate immune responses to the same IAV panel in human lung-resident dendritic cells. The aim of project III is to develop predictive modular multi-scale models for each cell type to understand the interplay of host and virus mechanisms in shaping the immune response at the level of individual cells and in the context of the lung. Critical to the success of the modeling efforts is the availability of data that have undergone standardized analyses to ensure consistency and high quality. Complementing the skills of the investigators in the experimental and modeling projects, the Model and Data Management Core will provide crucial bioinformatics expertise necessary to provide such analyses for all data and, in particular, for complex high-throughput data. Additionally, the realization of the overall program objectives is contingent upon the implementation of a centralized data storage and management resource that will serve as a gateway for organized access to the data by investigators in all research projects and cores. Finally, the Core will ensure that data and models generated within the scope of this application are effectively disseminated to the broader scientific community.